Identification of tryptophan metabolism-related biomarkers for nonalcoholic fatty liver disease through network analysis.

BACKGROUND

Increasing evidence demonstrates that tryptophan metabolism is closely related to the development of nonalcoholic fatty liver disease (NAFLD). This study aimed to identify specific biomarkers of NAFLD associated with tryptophan metabolism and research its functional mechanism.

METHODS

We downloaded NAFLD RNA-sequencing data from GSE89632 and GSE24807, and obtained tryptophan metabolism-related genes (TMRGs) from the MsigDB database. The R package limma and WGCNA were used to identify TMRGs-DEGs, and GO, KEGG and Cytoscape were used to analyze and visualize the data. Immune cell infiltration analysis was used to explore the immune mechanism of NAFLD and the biomarkers. We also validated extended levels of biomarkers.

RESULTS

We identified 375 NAFLD differentially expressed genes (DEGs) and 85 TMRGs-DEGs. GO/KEGG analysis revealed that TMRGs-DEGs were mainly enriched in triglyceride and cholesterol metabolism. ROC curves identified CCL20 (AUC = 0.917), CD160 (AUC = 0.933) and CYP7A1 (AUC = 1) as biomarkers of NAFLD. Immune infiltration analysis showed significant differences in ten immune cells, and the activation of dendritic cells and mast cells were highly positively correlated with NAFLD. CCL20, CD160 and CYP7A1 were highly correlated with M2 macrophage, neutrophil and mast cells activation, respectively. Twenty-seven TMRGs correlated with hub genes, and gene set enrichment analysis demonstrated their function in tryptophan- and lysine-containing metabolic process. We identified 41 therapeutic drug matches which corresponded to two hub genes and four drugs which co-targeted CCL20 and CYP7A1. Finally, three hub genes were validated in our mouse model.

CONCLUSIONS

CCL20, CD160 and CYP7A1 are tryptophan metabolism-related biomarkers of NAFLD, related to glycerol ester and cholesterol metabolism. We screened four compounds which co-target CCL29 and CYP7A1 to provide potential experimental drugs for NAFLD.